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Exome Sequencing Study Identifies Chromatin Remodeling-related Mutations in Schizophrenia

NEW YORK (GenomeWeb) – De novo mutations linked to schizophrenia are over-represented in chromatin remodeling genes, researchers from Cold Spring Harbor Laboratory and Trinity College Dublin reported in Molecular Psychiatry today.

Additionally, the researchers found that a number of those genes overlap with genes previously associated with autism and intellectual disability, possibly, the researchers said, indicating a common genetic etiology among the disorders.

Through exome sequencing of 57 parent-child trios with either sporadic or familial schizophrenia, the researchers led by Trinity College's Aiden Corvin set out to determine the role of de novo mutations in schizophrenia risk.

"These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis, and treatment of mental disorders," Corvin and his colleagues wrote in their paper.

Schizophrenia affects slightly more than 1 percent of the adult US population, though according to the National Institute of Mental Health, it occurs in 10 percent of people with a first-degree relative with the disorder. Corvin and his colleagues noted that previous genome-wide association studies have linked some 20 common loci to schizophrenia, though those common risk variants account for only a quarter of the genetic contribution to schizophrenia risk.

To uncover de novo mutations involved in schizophrenia, Corvin and his colleagues performed whole-exome sequencing on 42 sporadic schizophrenia and 15 familial schizophrenia parent-offspring trios.

Using the Illumina HiSeq 2000 platform, the researchers sequenced these 172 participants to a mean 67x coverage. From this, they found 59 exonic de novo variants including 58 de novo SNVs and one de novo dinucleotide variant that they validated through Sanger sequencing.

Of the 47 variants identified in the sporadic cases, 33 were classified as either missense or nonsense mutations, while of the 12 variants identified in the familial cases 10 were classified as missense mutations. Using haploinsufficiency and Residual Variation Intolerance Score (RVIS) analysis, they prioritized those mutations based on likely functional impact.

Top-ranking RVIS scored genes with nonsense de novo mutations from sporadic trios — genes that also had higher probability of haploinsufficiency — included the chromodomain helicase DNA-binding protein 8 (CDH8), autism susceptibility locus 2 (AUTS2), and the histone lysine methyltransferase 2 (MLL2) genes.

Further, using Neurocarta, Corvin and his colleagues noted that ontologies related to autism and intellectual disability were overrepresented among the de novo mutations they uncovered, even when controlling for gene size and GC content. Genes related to those ontologies included CHD8, AUTS2, MECP2, HUWE1, and TRAPPC9. The CHD8, MECP2, and HUWE1 genes, the researchers noted, are all involved in chromatin modification.

"Mutations were especially enriched in chromatin-modifying genes already implicated in mental disorders such as CHD8, MECP2, and HUWE1, suggesting the importance of genes that have evolutionarily impacted the epigenetic regulation of brain development and cognitive function in humans as having a shared central role in the susceptibility to, pathogenesis, and treatment of neurodevelopmental diseases," they added.

Using an additional set of nine studies that examined the exomes of autism and intellectual disability trios and six control sets, the researchers confirmed their suspicion that there was an increase in nonsense mutations in the disease cohorts, higher numbers of haploinsufficient genes, and an over-representation of mutations linked to autism and intellectual disability ontologies.

The researchers cautioned, though, that neurodevelopmental disorders capture a lot of heterogeneity and that studies involving larger cohorts will be needed to better examine the similarities and differences among these groups of patients.